Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Science for Life Laboratory, Linköping University , Linköping, Sweden.
J Gen Physiol. 2024 Jul 1;156(7). doi: 10.1085/jgp.202313516. Epub 2024 Jun 4.
Voltage-gated ion channels are responsible for the electrical excitability of neurons and cardiomyocytes. Thus, they are obvious targets for pharmaceuticals aimed to modulate excitability. Compounds activating voltage-gated potassium (KV) channels are expected to reduce excitability. To search for new KV-channel activators, we performed a high-throughput screen of 10,000 compounds on a specially designed Shaker KV channel. Here, we report on a large family of channel-activating compounds with a carboxyl (COOH) group as the common motif. The most potent COOH activators are lipophilic (4 < LogP <7) and are suggested to bind at the interface between the lipid bilayer and the channel's positively charged voltage sensor. The negatively charged form of the COOH-group compounds is suggested to open the channel by electrostatically pulling the voltage sensor to an activated state. Several of the COOH-group compounds also activate the therapeutically important KV7.2/7.3 channel and can thus potentially be developed into antiseizure drugs. The COOH-group compounds identified in this study are suggested to act via the same site and mechanism of action as previously studied COOH-group compounds, such as polyunsaturated fatty acids and resin acids, but distinct from sites for several other types of potassium channel-activating compounds.
电压门控离子通道负责神经元和心肌细胞的电兴奋性。因此，它们是调节兴奋性的药物的明显靶点。激活电压门控钾 (KV) 通道的化合物有望降低兴奋性。为了寻找新的 KV 通道激活剂，我们在专门设计的 Shaker KV 通道上对 10000 种化合物进行了高通量筛选。在这里，我们报告了一个带有羧基 (COOH) 基团的常见基序的大型通道激活化合物家族。最有效的 COOH 激活剂具有亲脂性（4 < LogP <7），并被建议结合在脂质双层和通道的带正电荷的电压传感器之间的界面上。COOH 基团化合物的带负电荷的形式通过静电将电压传感器拉到激活状态来打开通道。几种 COOH 基团化合物还可激活治疗上重要的 KV7.2/7.3 通道，因此可潜在地开发为抗癫痫药物。本研究中鉴定的 COOH 基团化合物被认为通过与先前研究的 COOH 基团化合物（如多不饱和脂肪酸和树脂酸）相同的位点和作用机制起作用，但与其他几种钾通道激活化合物的位点不同。
